This is competing renewal application of grant 1 U01 MH69062 in response to Program Announcement PAR-08-238 (NCDDDG). The main objectives of this project are now focused on the synthesis, and in vitro and in vivo characterization of novel y-aminobutyric acid (GABA) B receptor positive modulators for the treatment of nicotine dependence. The proposed program consists of three Scientific Projects and an Administrative Core (U19) (PD: A. Markou). Project 1 (PI: M.G. Finn, The Scripps Research Institute, La Jolla, California) will design, synthesize, and refine new GABAB receptor positive modulators, using both combinatorial and click chemistry. Project 2 (PI: P. Griffin, The Scripps Research Institute, Jupiter, Florida), will profile the in vitro pharmacology of candidate GABAB receptor positive modulators using cell-based functional G-protein coupled receptor (GPCR) assays for GABAB receptors. Project 2 will also assess the in vitro metabolism, and in vivo brain penetration and pharmacokinetic characteristics of selected compounds. Compounds with the desired combination of properties will be tested in Project 3 (PI: A. Markou, Univ of California San Diego, La Jolla, California) in well validated rat models of nicotine dependence. These in vivo models will include nicotine self-administration, reward-enhancing effects of nicotine in the intracranial self-stimulation procedure, cue-induced reinstatement of nicotine-seeking and anxiety-like behavior during nicotine withdrawal. Extensive work during the previously funded period resulted in the first highly selective positive modulators for GABAB receptors with the desired behavioral effects in rat models of nicotine dependence. Thus, strong preclinical proof-of-concept has been established for the unique and novel strategy of GABAB receptor positive modulation in the treatment of nicotine dependence, and potentially dependence on other drugs of abuse. With this application, we seek funding to build on our previous results by: (a) expanding the pipeline of drug-like active agents;(b) understanding the factors that promote selective positive modulation of GABAB receptors;and (c) assessing how the newly synthesized compounds affect behaviors in rat models of nicotine dependence. This multidisciplinary research program integrates the complementary expertise of the participating scientists to provide innovative potential therapeutics for nicotine dependence in humans.